2-bromo-dihydro allohydrocortisone



2,942,011. g-BRQMO-DIHYDRO ALLOHYDROCORTISONE George ,Krsek, Danville,Pa., assignor to Merck & Co.,

lnc Rahvvay, N.J., 'a corporation of New Jersey No' Drawing. Filed Nov.16, 1955, Ser. No. 547,297

3 Claims. 01. 260-39745) This invention is concerned generally withallopregnane compounds and with processes for preparing them. Moreparticularly, it relates to novel A-3,20-diketo-115,17a-dihydroxy-Zl-oxygenated-allopregnenes, and withnovel processes of preparing these compounds starting with 3,20-diketo-11l9,17a-dihydroxy-2 l-acyloxypregnane.

"The new compounds, A -3,20-diketo-11fl,17a-dihydroxy-21-acyloxy-al1opregnenes, may be chemically represented follows: p i

wherein R is an acyl radical. These A -3,20-diketo-1'15,17a-dihydroxy-2l-acyloxy-allopregnenes have been demonstrated topossess extremely high local cortisone activity accompanied bypractically no systemic action. They are thus of particular value in thetreatment of conditions which heretofore respond to the localadministration of cortisone and'hydrocortisone, without the productionof side effects such as edema which can be caused by the sodiumretention action of cortisone and hydrocortisone.

i The. A -.3,20-diketo-115,17a-dihydrdxy-2l-acyloxy-allopregnenes,subject of the present invention, can be prepared by reacting"3,20-diketo-11B,17m-dihydroxy-21-acyloxy-allopregnane (Compound 1hereinbelow) with a halogenating agent to form2-halo-3,20-diketo-11B,17adihydroxy-Zl-acyloxy-allopregnane (Compound2), which is then reacted with a dehydrohalogenating agent to produce A4 3,20-diketo-11p,17a-dihydroXy-2l-acyloxy-allopregnene, (Compound 3).

- fT-he reactions indicated hereinabove may be chemically represented asfollows: a

Compound 1 2,942,011 Patented June 21, 1960 OHQOR CHzOR $0 J20 '----orr'----011 HO HO x I Compound 2 Compound 3 wherein X stands for a haloradical, and. R has the significance above-defined.

The 3,20 diketo-l 1/8,l7a-dihydroxy-2l-acyloxy-allopregnanes used asstarting materials include 3,20-diketo-11/8,17a-dihydroxy-21-alkanoyloxy-allopregnane,3,20-diketol1B,17a-dihydroxy-2l-acetoxy-allopregnane, 3,20-diketo1lB,l7a-dihydroXy-2l-propionoxy-allopregnane, 3, 20diketo-l1B,l7a-dihydroxy-2l-heptanoyloxy-allopregnane, 3,20 diketo11/8,17a-dihydroXy-2l-benzoXy-allopregnane, and the like.

The halogenation of the3,20-diketo-l1B,l7a-dihydroxy-Zl-acyloxy-allopregnane is convenientlyconducted utilizing a halogenating agent of the positive halogen type,such as bromine, N-bromoamides, chlorine, N- chloroamides, tertiarybutyl hypochlorite, and the like. When bromine or chlorine is used asthe halogenating agent, the halogenation reaction is ordinarily carriedout by dissolving the3,20-diketo-11B,l7a-dihydroXy-21-acyloxy-allopregnane in a solvent inertto the halogen and adding the halogen to the resulting solution. It isordinarily preferred to carry out the halogenation at room temperatureby adding a solution of the halogen in glacial acetic acid, dropwise, toa solution of the 3,20-diketo- 11/8,17a-dihydroxy2l-acyloXy-allopregnanein a mixture of chloroform and glacial acetic acid containing a smallamount of p-toluene sulfonic acid. The product is recovered from thehalogenation mixture by evaporating the solvent and recrystalliz'ing theresidual material from a solvent such as acetonitrile to give thedesired 2-halo- 3,20 diketo-l1p,17a-dihydroxy-21-acyloxy-allopregnane asfor example 2-bromo-3,20-diketo-llB,l7a-dihydroxy- 21alkanoyloXy-allopreg'nane, 2bromo-3,20-diketo-1l,8,17a-dihydroxy-2l-acetoxy-allopregnane, 2-bromo-3,20-diketo11B,l7u-dihydroxy21-propionoXy-allopregnane, 2- bromo3,20-diketo-l113,17u-dihydroXy-2l-benzoxy-allopregnane, and the like.

The dehydrohalogenation of the 2-halo-3,20-diketo-11,8,l7a-dihydroxy-21-acyloxy-allopregnane thus formed can be carriedout, if desired, by reacting this compound with a tertiary amine such aspyridine, collidine, and

the like. It is preferred, however, to utilize semicarbathen reactedwith. a solution of pyruvic acid in acetic acid at room temperature orabove if desired. At room temperature, the hydrolysis of the3-semicarbazone is ordinarily complete in about sixteen hours. Thehydrolysis product is conveniently recovered by diluting the hydrolysissolution with water and extracting the aqueous mixture with chloroform.The chloroform extract is washed with water, with an aqueous alkalinesolution to remove impurities; and dried. The dry chloroform solution isthen evaporated to give A-3,20-diketo-l1B,17u-dihydroxy-2l-acyloxy-pregnene, which can bepurified by chromatography followed by recrystalliza tion fromacetone-petroleum ether.

This A 3,20 diketo 11,8,170; dihydroxy 21 acyloxy-pregnane isconveniently hydrolyzed by reaction with a methanolic solution ofpotassium bicarbonate to form A-3,20-diketo-11p,17a,2l-trihydroxy-pregnene. The latter compound maythen be treated with an acylating agent, preferably a carboxylic acylanhydride as for example a lower alkanoic acid anhydride such as aceticanhydride, propionic anhydride, heptanoic anhydride, benzoic anhydride,an alicylic anhydride such as .cyclopentapropicnic anhydride, analiphatic dicarboxylic acid anhydride such as succinic anhydride,glutaric anhydride, 5,,8-dimethylglutaricanhydride, maleic anhydride,adipic anhydride, an aromatic dicarboxylic acid anhydride such asphthalic anhydride, and the like. The reaction between the A3,20-diketo-11,B,17a,21-trihydroxy-pregnene and the carboxylic acylanhydride, or if preferred the corresponding carboxylic acid halogenide,is conveniently carried out in the presence of a tertiary amine such asdimethylaniline or pyridine, thereby acylating the 2l-hydnoxysubstituent. The acylated product is readily separated from reactionmixture by evaporating the liquid components and recrystallizing theresidual material from a solvent such as ethyl acetate to givesubstantially pure A -3,20-diketo 11B,17ad-ihydroxy-2l-acyloxy-allopregnene, as for example A 3,20 diketo11,8,l7ot dihydroxy 21 alkanoyloxy-allopregnene,

A 3,20 diketo 113,17a dihydroxy 21 acetoxy allopregnene,

A 3,20 diketo 1119,1700

onoxy-allopregnene,

A 3,20 diketo 116,17 dihydroxy 21 butyroxy allopregnene,

A 3,20 diketo 115,17a dihydroxy 21 heptanoyloxy-allopregnene,

A 3,20 diketo 115,170: dihydroxy 21 benzoxy allopregnene,

A 3,20 diketo-11fl,17a,21 trihydroxy allopregnene 21-hemisuccinate,

A 3,20 diketo 1lfi,17a,21 t-rlhydroxy allopregnene21-hemi-/3,,6-dimethylglutarate,

A 3,20 diketo 11fi,17a,21 trihydroxy allopregnene21-cyclopentapropionate. e

- dihydroxy 21 propiand the like.

The following examples illustrate methods of carrying out the presentinvention, but it is to be understood that these examples are given forpurposes of illustration and not of limitation.

Example 1 To 813 mg. of3,20-diketo-11B,17u-dihydroxy-2lacetoxy-allopregnane (2.00 millimol) in20 m1. chloroform at 15 C. is added 4.8 ml. of 0.5 N p-toluenesulfonicacid in acetic acid. To the stirred mixture is added dropwise 320 mg. ofbromine (2.00 millimol) and 180 mg. sodium acetate (2.2 millimol) in m1.acetic acid. The addition and decolorization are complete in about 5minutes, following which a solution of 180 mg. sodium acetate in 3 ml.water is added. Additional water is added, and the reaction mixture isextracted 4 with chloroform. The chloroform extract is washed withwater, potassium bicarbonate solution, and water. The neutral chloroformextract is dried, and the solvent is evaporated in vacuo. The residualmaterial is triturated with acetonitrile and the crystalline materialwhich precipitates is recovered by filtration and purified byrecrystallization from acetonitrile to give substantially pure 2 bromo3,20 diketo 1119.171: dihydroxy 21 acetoxy-allopregnane; M.P.-189190 C.

Example 2 To 2-bromo-3,2Odiketo-11 3,17adihydroxy-21 acetoxyallopregnane(300 mg.) in 30 ml. .acetonitrile is added under nitrogen 171 mg.semicarbazide hydrochloride and 117 mg. sodium bicarbonate in 1 ml.water. After'two hours at 25 C., the stirred solution is evaporated invacuo to a thick slurry, and 50 ml. water is added. The solid materialis recovered by filtration, washed with water, and dried to give A-3,20-diketo-111S,17u-dihydroxy-21-acetoxy-allopregnene-3-semicarbazone;

max

AGHKOH 2650A., E% 474 I pregnene 3-semicarbazone obtained as describedin Example 2, is dissolved in 11 m1, acetic acid, 2.8 1111. water and0.8 m1. pyruvic acid. After sixteen hours at-ro'om. temperature water isadded, and the aqueous mixture is extracted with chloroform. Thechloroform extract is washed with water, dilute potassium bicarbonatesolution and saturated aqueous sodium chloride solution, and dried withanhydrous magnesium sulfate. The solvent is evaporated in vacuo, theresidual material is dissolved in 1:1 benzene-chloroform and thesolution passed through neutral alumina thereby recovering a smallamount of polar impurity. The benzene-chloroform solution is evaporatedto dryness in vacuo, and the residual material is recrystallized fromacetone-petroleum ether to give substantially pure A -3,2O-diketo-11fi,17oc dihydroxy-Zl-acetoxy-allopregnene in the form of glistening"plates; M.P. 225230 C. dec.;

xgg 2280, E% 265 Analysis.Calcd. for c n o c, 68.29; H, 7.98. Found: C,68.51;,H, 8.14.

Example 4 One hundred milligrams of A-3,20-diketol1B,].7a-dihydroxy-2l-acetoxy-allopregnene is dissolved in ature of 1.0 cc. of benzene and 1.0 cc. of 1.1 N methanolici potassiumhydroxide, and the solution is allowed to stand at room temperature fora period of about 10 minutes.- The solution is then acidified withacetic acid, the bon zene is evaporated in vacuo, and the residualmaterial is recrystallized from ethyl acetate to give substantially pureA -3,20-diketo-1 15,170,2l-trihydroxy-allopregnene.

. Various changes and modifications may be made in carrying out thepresent invention without departing from the spirit and scope thereof.Insofar as these changes and modifications are within the purview of-theannexed claims, they are to be considered as part of this invention.

I claim:

1. 2-halo3,20-diketo-1If ,17a-dihydroxy-21-lower 11y? drocarboncarbonyloxy-allopregnane. 1 e

2. 2-bromo-3 ,20-diketo-1 l f3,l7adihydroxy-21-1oWeralkanoyloxy-allopregnane.

3. 2 brorno 3,20 diketo 115,170: diliydroxy 7 21 acetoxy-allopregnane.

(References on following page) References Cited in the file of thispatent UNITED STATES PATENTS Kendall Apr. 1, 1952 Herzog Mar. 6, 1956Sondheimer June 19, 1956 Wilson et a1. Dec. 4, 1956 Walker Apr. 22, 1958Hirschmann et a1 May 5, 1959 OTHER REFERENCES Experiential, Kaufman etaL, vol. 7 (1951), page 260.

Djerassi: Jour. Am. Chem. 80s., 69: 2404-2410 (1947).

Rosenkranz: Jour. Am. Chem. $00., 7.2: 1046 (1950); 4077-4080 (1950);75: 1277-1282 (1953).

1. 2-HALO-3,20-DIKETO-11B,17A-DIHYDROXY-21-LOWER HYDROCARBON CARBONYLOXY-ALLOPREGNANE. 